Abstract 1894: Preclinical development of YL205, a novel NaPi2b-targeting antibody-drug conjugate (ADC) with novel topoisomerase I inhibitor-based linker-payload for treatment of solid tumors

Abstract MediLink’s TMALIN (Tumor Microenvironment Activable LINker-payload) platform incorporates the proprietary protease-cleavable tripeptide linker and novel DNA topoisomerase I inhibitor, enables the release payload both in the tumor cell intracellularly and in the tumor microenvironment extracellularly. YL205 is built on the TMALIN platform, which is comprised of an anti-NaPi2b humanized monoclonal antibody and conjugated in a site-specific manner to yield a uniform DAR 8 product. NaPi2b, encoded by the SLC34A2 gene, is a cell surface sodium-dependent phosphate transporter that is highly expressed in certain cancers, including ovarian, lung, thyroid, and breast cancers, with limited expression in normal tissues. This study evaluated the drug properties, efficacy, safety and pharmacokinetic profiles of YL205 in nonclinical studies. YL205 achieved a high drug-to-antibody ratio through homogeneous conjugation with hydrophilic TMALIN linker-payload, which showed limited impact on the hydrophilicity of the antibody, prolonged the retention time in vivo and eventually enhanced the in vivo potency of ADC. Additionally, YL205 exhibited strong potency, high internalization, potent cytotoxicity and bystander-mediated cell killing toward tumor cells. Significant dose-dependent antitumor activities, including complete tumor regressions with no observable toxicity, were noted in NaPi2b low to high expression ovarian and NSCLC tumor xenograft mouse models. YL205 showed a favorable PK profile evidenced by the overlapping ADC and TAb curves in SD rat and cynomolgus monkey studies. Despite high levels of expression in normal lungs of non-human primates, YL205 exhibited a good safety profile with toxic findings unrelated to normal tissue target expression. Toxicity studies using cynomolgus monkeys showed that YL205 is well tolerated with calculated therapeutic index (TI, HNSTD versus MED) of ﹥80 for repeat dosing. No drug-related adverse findings were found in the lungs, liver or kidneys when tested in all doses. The highly stable nature of TMALIN linker, together with the high potency of the payload, likely mitigates the potential liability of this normal tissue expression. Based on these results, it demonstrates that YL205’s advanced ADC design results in an increased therapeutic margin, and YL205 may help address unmet medical need in patients with NaPi2b-expressing tumors. Citation Format: Liang Xiao, Wei Lian, Qigang Liu, Qing Zong, Shuai Song, Sasha Stann, Jiaqiang Cai, Tongtong Xue. Preclinical development of YL205, a novel NaPi2b-targeting antibody-drug conjugate (ADC) with novel topoisomerase I inhibitor-based linker-payload for treatment of solid tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 1894.